This invention relates to a process for the preparation of 1,6-dichloro-1,6-dideoxy-.beta.-D-fructofuranosyl-4-chloro-4-deoxy-.alpha. -galactopyranoside. This compound is a potent sweetener, having a sweetness several hundred times that of sucrose. Its use as a sweetener and in sweetening compositions is disclosed in U.S. Pat. No. 4,435,440.
The preparation of 1,6-dichloro-1,6-dideoxy-.beta.-D-fructofuranosyl-4-chloro-4-deoxy-.alpha. -galactopyranoside or as it is sometimes referred to in the literature, 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose, (hereinafter referred to as "sucralose") involves the substitution of chlorine atoms in the sucrose molecule in one of the five secondary hydroxyl positions and in two of the three primary hydroxyl positions. This particular selection of positions usually means that any synthetic route must involve the preparation of an intermediate sucrose derivative having the required positions available for chlorination while the other positions are blocked. In particular, the reactive 6-position must not be chlorinated, while the 4-position must be rendered available for chlorination.
One route proposed in the literature (Fairclough et al, Carbohydrate Research 40 (1975) 285-298) involves the formation of the 6,1',6'-tritrityl derivative of sucrose, peracetylation of the molecule and then detritylation with migration of the 4-acetyl radical to the 6-position, to give 2,3,6,3',4'-penta-O-acetylsucrose which has the correct hydroxy groups unprotected. Subsequent reaction with a chlorinating agent provides the 4,1',6'-trichlorogalactosucrose penta-acetate which in turn yields sucralose on removal of the acetyl groups. The chlorination proceeds with inversion of configuration at the 4-position. The 1' and 6'-positions freely rotate, but the 4-position cannot and the glucose ring is thus inverted at the 4-position yielding a galactose derivative so that the product is a galactosucrose.
Another route is set forth in U.S. Pat. No. 4,380,476 and comprises the steps of: (a) reacting sucrose with an acylating reagent under conditions to provide a mixture of acylated sucrose derivatives containing a major proportion of 6-monoacylated material; (b) optionally separating the 6-monoacylated sucrose derivative from other acylated derivatives before step (c); (c) reacting the monoacylated sucrose derivative with a chlorinating reagent capable of chlorinating at positions 1', 4 and 6' of a sucrose 6-acylate; and (d) deacylating and separating (in either order) the sucralose material formed.
A further process for preparing sucralose is set forth in U.S. Pat. No. 4,362,869. This process converts sucrose through a number of steps into sucralose. This process describes the sequential steps of (1) tritylation of sucrose to block the three primary alcohol groups; (2) acetylation of the five secondary alcohol groups as acetates; (3) detritylation of the three primary alcohol groups to deblock them; (4) acetyl migration from the 4-position to the 6-position; (5) chlorinating the desired alcohol groups at positions 4, 1', 6'; and (6) deblocking the remaining five alcohol groups by deacetylation thereby yielding sucralose.
The invention disclosed in U.S. Pat. No. 4,362,869 is centered around the acetyl migration from the 4-position to the 6-position which is effected by treating a solution of 2,3,4,3',4'-penta-O-acetyl sucrose in an inert solvent with a weak acid at an elevated temperature. It was found that selection of specific reaction conditions for the acetyl migration gave considerably higher yields overall for separate detritylation and migration than the prior art which taught a one stage process for these steps. The weak acid utilized is preferably a carboxylic acid, especially an aliphatic carboxylic acid such as acetic acid. It is stated that any acid having an acid strength of the same order as acetic acid under the conditions used will suffice. The reaction temperature should be elevated above ambient temperature in order to provide an acceptable reaction time. A temperature of from about 80.degree. to 150.degree. C. is said to be suitable, preferably 100.degree. to 130.degree. C.
The inert solvent is said to be any solvent for penta-O-acetyl sucrose which remains liquid at the elevated temperature selected, e.g. a temperature in the range of 100.degree. to 140.degree. C. Ketonic solvents are particularly preferred, especially methyl isobutyl ketone, which refluxes at about 117.degree. C. A dilute solution of the acid in the solvent is said to be suitable, e.g. a solution of from 2 to 10% by weight, especially about 5%. This degree of dilution is suitable for reaction with the sucrose penta-acetate dissolved at a concentration of up to 30% by weight, e.g. about 20%. Ester solvents of sufficiently high boiling point are also useful, e.g. n-butyl acetate. Also of particular interest are aromatic hydrocarbons such as toluene or xylene.
When the reaction is completed, the reaction mixture is cooled an 2,3,6,3',4'-penta-O-acetylsucrose crystallizes. After an additional period of time at 0.degree. C., the crystalline product is filtered, washed and dried and then proceeds to the chlorination step. While an effective process, the above process involves the use of a carboxylic acid at high temperatures in the presence of free hydroxyl groups, conditions known to promote acylation.
The prior art also reveals that dilute aqueous solutions of bases are suitable for carrying out acetyl migrations. Although a migration occurs from the 4 to the 6 positions of the glucose ring with 0.001 N sodium hydroxide, the yield is very low due to concurrent deacetylation. When 2 to 5% solutions of a very weak base, pyridine or substituted pyridines, e.g. 2,4 and 2,6 lutidines or 2,4,6 tri-methyl pyridine (collidine) are used in water, reasonable yields of 2,3,6,3',4'-penta-O-acetyl sucrose are obtained, however, deacetylation and further migration to give 3,4,6,3',4'-penta-O-acetyl sucrose also occurs.
It is an object of the present invention to provide an improved process for the preparation of sucralose.
It is a further object of the present invention to provide a process for the preparation of sucralose wherein the acetyl migration step of U.S. Pat. No. 4,362,869 can be accomplished without utilizing a weak acid.
These and other objects of the present invention will become apparent to one skilled in the art from the detailed description given hereinafter.